The mechanism(s) responsible for the therapeutic effect of antidepressant drugs is not completely understood. One current view regarding the pathology of depression proposes that this mental illness results from dysfunction of synaptic connections, perhaps due to the loss of synaptic contacts. Conversely, recent experimental data have suggested that the therapeutic action of antidepressants may involve their ability to increase neurogenesis and synaptic strength. These properties may result more from the induction of neurotrophic factor synthesis than activation of monoamine receptors. This suggestion is supported by preliminary data showing that antidepressants increase the synthesis of basic fibroblast growth factor (FGF2), a neurotrophic factor that exerts neurotrophic activity on catecholaminergic neurons and promotes neurogenesis in the adult brain. These experimental data give rise to a novel and challenging but timely hypotheses that depression is characterized by lack of trophic support and that antidepressants restore synaptic plasticity in adult brain by inducing the synthesis of FGF2. As an experimental tool to test these hypotheses, we propose to use a rat model of depression termed chronic, unpredictable mild stress (CMS), by which rats develop anhedonia, one of the core symptoms of major depression. In particular, we plan to investigate whether CMS down-regulates FGF2 expression (mRNA and protein) in the brain and whether antidepressants such as desipramine and fluoxetine will reverse this down-regulation. Moreover, since CMS evokes apoptotic cell death in the frontal cortex, we propose to test the neuroprotective activity of antidepressants in this animal model of depression by examining the ability of antidepressants and FGF2 to limit apoptotic cell death. Apoptosis will be determined by measuring caspase- 3 activation and in situ terminal deoxynucleotidyl transferase-mediated biotinylated DTP nick end labeling (TUNEL) staining in several brain areas of CMS rats. Overall, the results of the present study will provide a major break-through on the mechanisms whereby antidepressants affect neuronal plasticity in mature rats. Data from this proposal may help elucidate the therapeutic efficacy of antidepressants in affective disorders. [unreadable] [unreadable]